2--1H-thienoimidazoles. A Novel Class of Gastric H+/K+-ATPase Inhibitors

Article abstract of DOI:10.1021/jm00081a004

2-<(2-Pyridylmethyl)sulfinyl>thienoimidazoles were synthesized and investigated as potential inhibitors of gastric H⁺/K⁺-ATPase.The <3,4-d>isomers of the two possible thienoimidazole series were found to be potent inhibitors of gastric acid secretion in vitro and in vivo.Structure-activity relationships indicate that especially lipophilic alkoxy, benzyloxy, and phenoxy substituents with additional electron-demanding properties in the 4-position of the pyridine moiety combined with an unsubstituted thieno<3,4-d>imidazole lead to highly active compounds with a favorable chemical stability.Various substitution patterns in the thieno<3,4-d>imidazole moiety result in lower biological activity.The heptafluorobutyloxy derivative saviprazole (HOE 731, 5d) was selected for further development and is currently undergoing clinical evaluation.Comprehensive pharmacological studies indicate a pharmacodynamic profile different to omeprazole, the first H⁺/K⁺-ATPase blocker introduced on the market.